BLR&D Research Career Scientist Award

BLR

基本信息

批准号：
10265373
负责人：
Gianfranco D Alpini
金额：
--
依托单位：
RLR VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10265373
关键词：
Alcoholic Liver Diseases Angiogenic Factor Area Award Basic Science Bile Duct Epithelium Biliary Calcitonin Gene-Related Peptide Cell Aging Cells Cholangiocarcinoma Cholestasis Chronic Clinical Clinical Sciences Collaborations Cyclic AMP Data Development Diagnosis Disease Disease Progression Ductal Epithelial Cell Educational process of instructing Epithelial Cells Faculty Fatty Alcohols Fatty Liver Fibrosis Foundations Funding Gastroenterology Gastrointestinal Diseases Genes Goals Grant Grant Review Growth Health Hepatic Stellate Cell Hepatobiliary Hepatology Heterogeneity Homeostasis Human In Vitro Inflammation Intervention Investigation Journals Knowledge Liver Cirrhosis Liver Failure Liver Fibrosis Liver diseases Mediating Medical Medical Students Medical center Melatonin Mentors MicroRNAs Modeling Molecular Nature Neoplastic Cell Transformation Neuropeptides Neurosecretory Systems Neurotransmitters Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phenotype Play Population Postdoctoral Fellow Prevention Primary biliary cirrhosis Program Development Proliferating Publications Publishing Reaction Regulation Research Research Personnel Rodent Rodent Model Role Sampling Scientist Secretin Seminal Sensory Serotonin Serum Services Signal Pathway Signal Transduction Substance P Therapeutic Agents Therapeutic Intervention Training United States National Institutes of Health Veterans Viral afferent nerve autocrine base bile duct biliary tract career cell injury cholangiocyte cholestatic liver disease chronic liver disease clinically relevant editorial graduate student in vivo liver injury liver transplantation meetings member neuroendocrine phenotype non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel paracrine peptide P primary sclerosing cholangitis problem drinker prognostic tool programs receptor repaired response secretin receptor senescence stem cells symposium therapeutic development therapeutically effective therapy development tissue injury

项目摘要

Bile duct epithelial cells (i.e., cholangiocytes) are the target cells in cholangiopathies such as primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and cholangiocarcinoma (CCA), which are diseases characterized by the damage, proliferation and neoplastic transformation of cholangiocytes. These cholestatic liver diseases (characterized by coordinated proliferation/damage of biliary epithelial cells) along with other cholangiopathies represent a major clinical challenge due to the lack of effective therapeutic interventions resulting in the need for liver transplantation during end-stage liver disease. Management of cholangiopathies (including drug- or viral-induced liver injury) represents one of the major challenges for Veterans Health. Targeting the neuroendocrine factors that respond to cholestasis resulting from tissue injury may help limit inflammation and fibrosis that occur during hepatobiliary damage. There is a critical need to understand the neuroendocrine triggers of cholangiocyte growth and their responses to damage during cholestasis, which will help identify key signaling pathways that represent viable targets for the development of effective therapeutic agents. Our long-term research goal is to develop an understanding of the neuroendocrine factors and signaling mechanisms regulating biliary growth during cholestasis, fatty liver and alcohol-induced liver disease, which will provide a foundation for the discovery of prevention and new pharmaceutical interventions for cholangiopathies and liver diseases characterized by hepatic fibrosis. For my current funded VA Merit Award, the central hypothesis is based upon the postulate that the secretin/secretin receptor (Sct/SR) axis signaling is key for mediating the proliferative and activated profibrogenic biliary phenotype that contributes to the progression of hepatic steatosis and fibrosis during the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). In addition, my research program is funded by multiple collaborative NIH R01 grants that explore various aspects of the regulation of biliary growth and hepatic fibrosis by neuroendocrine factors such as secretin, melatonin, serotonin and miRNAs in models of cholestasis, NAFLD, and alcohol-induce liver disease. My collaborative effort with multiple VA investigators has been high productive and has resulted in many publications in high impact journals. The exploration of the neuroendocrine features of cholangiocytes will provide new avenues for the development of therapeutic interventions for these diseases. Our contribution is significant since this is a critical step to provide translational knowledge for the development of therapies for cholangiopathies. These findings will also have broader implications for other hepatic diseases characterized by hepatic fibrosis.

胆管上皮细胞（即胆管细胞）是原发性胆汁性胆管病等胆管病的靶细胞胆管炎（PBC）、原发性硬化性胆管炎（PSC）和胆管癌（CCA）以胆管细胞损伤、增殖和肿瘤转化为特征的疾病。这些胆汁淤积性肝病（以胆道上皮细胞协调增殖/损伤为特征）由于缺乏有效的治疗方法，细胞）与其他胆管病一起构成了重大的临床挑战。治疗干预导致终末期肝病期间需要进行肝移植。胆管病（包括药物或病毒引起的肝损伤）的治疗是主要的治疗方法之一退伍军人健康面临的挑战。针对对胆汁淤积作出反应的神经内分泌因子组织损伤引起的炎症和纤维化可能有助于限制肝胆损伤期间发生的炎症和纤维化。那里迫切需要了解胆管细胞生长的神经内分泌触发因素及其反应胆汁淤积期间的损伤，这将有助于识别代表可行目标的关键信号通路以开发有效的治疗药物。我们的长期研究目标是开发一种了解调节胆道生长的神经内分泌因子和信号机制胆汁淤积、脂肪肝和酒精性肝病，这将为这一发现提供基础胆管病和肝病的预防和新的药物干预措施通过肝纤维化。对于我目前资助的 VA 优异奖，中心假设是基于假设促胰液素/促胰液素受体 (Sct/SR) 轴信号传导是介导增殖的关键和激活的促纤维化胆道表型，有助于肝脂肪变性的进展非酒精性脂肪肝病（NAFLD）/非酒精性脂肪性肝炎发病机制中的纤维化（纳什）。此外，我的研究项目由多项 NIH R01 合作资助资助，旨在探索神经内分泌因素对胆道生长和肝纤维化的各个方面的调节，例如胆汁淤积、NAFLD 和酒精诱导肝脏模型中的促胰液素、褪黑激素、血清素和 miRNA 疾病。我与多名 VA 研究人员的合作非常富有成效，并取得了成果在高影响力期刊的许多出版物中。神经内分泌特征的探索胆管细胞将为这些疾病的治疗干预措施的开发提供新途径疾病。我们的贡献是重大的，因为这是为以下领域提供翻译知识的关键一步：胆管病疗法的开发。这些发现还将对以下领域产生更广泛的影响：以肝纤维化为特征的其他肝脏疾病。